Multifunctional N-fused fluorescent probes for detection of iron ions and nitro explosives.

In this work, two novel probes 4a and 4b were synthesized through Suzuki-Miyaura coupling reaction, whose structures were further confirmed by 1H NMR, 13C NMR, high-resolution mass spectrometry (HRMS) and X-ray single crystal diffraction. The optical properties of the obtained molecules were investigated accordingly. Owing to different bridging fluorophores, there are certain differences in optical performance and detection ability between the two synthesized compounds. Especially, due to the subtle difference in orbitals energy and electron distribution displayed by the DFT calculations, 4a possesses the characteristics of dual-state emission (DSE) molecule, while 4b is an aggregation-induced emission (AIE) molecule. Interestingly, these two molecules can be developed into multifunctional detection probes, successfully applied for the fluorescence recognition of iron ions and common nitroaromatic compounds (NACs). At the same time, the probe molecules can also be applied to the detection of NACs in aqueous environment. What's more, they can also be loaded on test strips and thin-films for fluorescence identification of NACs, thus being expected to be developed into portable detection tools for NACs.

Structured light analogy of quantum squeezed states.

Quantum optics has advanced our understanding of the nature of light and enabled applications far beyond what is possible with classical light. The unique capabilities of quantum light have inspired the migration of some conceptual ideas to the realm of classical optics, focusing on replicating and exploiting non-trivial quantum states of discrete-variable systems. Here, we further develop this paradigm by building the analogy of quantum squeezed states using classical structured light. We have found that the mechanism of squeezing, responsible for beating the standard quantum limit in quantum optics, allows for overcoming the "standard spatial limit" in classical optics: the light beam can be "squeezed" along one of the transverse directions in real space (at the expense of its enlargement along the orthogonal direction), where its width becomes smaller than that of the corresponding fundamental Gaussian mode. We show that classical squeezing enables nearly sub-diffraction and superoscillatory light focusing, which is also accompanied by the nanoscale phase gradient of the size in the order of λ/100 (λ/1000), demonstrated in the experiment (simulations). Crucially, the squeezing mechanism allows for continuous tuning of both features by varying the squeezing parameter, thus providing distinctive flexibility for optical microscopy and metrology beyond the diffraction limit and suggesting further exploration of classical analogies of quantum effects.

Natural Silkworm Cocoon-Derived Separator with Na-Ion De-Solvated Function for Sodium Metal Batteries.

The commercialization of sodium batteries faces many challenges, one of which is the lack of suitable high-quality separators. Herein, we presented a novel natural silkworm cocoon-derived separator (SCS) obtained from the cocoon inner membrane after a simple degumming process. A Na||Na symmetric cell assembled with this separator can be stably cycled for over 400 h under test conditions of 0.5 mA cm-2-0.5 mAh cm-2. Moreover, the Na||SCS||Na3V2(PO4)3 full cell exhibits an initial capacity of 79.3 mAh g-1 at 10 C and a capacity retention of 93.6% after 1000 cycles, which far exceeded the 57.5 mAh g-1 and 42.1% of the full cell using a commercial glass fiber separator (GFS). The structural origin of this excellent electrochemical performance lies in the fact that cationic functional groups (such as amino groups) on silkworm proteins can de-solvate Na-ions by anchoring the ClO4- solvent sheath, thereby enhancing the transference number, transport kinetics and deposition/dissolution properties of Na-ions. In addition, the SCS has significantly better mechanical properties and thinness indexes than the commercial GFS, and, coupled with the advantages of being natural, cheap, non-polluting and degradable, it is expected to be used as a commercialized sodium battery separator material.

Interactions between dissolved organic matter with different molecular weights and nonylphenol in surface water bodies.

Dissolved organic matter (DOM) has a complex composition, which can interact with various pollutants and affect the removal of pollutants. Therefore, a thorough understanding of the interaction between the encccvironmental hormone nonylphenol (NP) and DOM is crucial for environmental impact and development. In this study, the interaction was investigated by means of excitation emission matrix (EEM) fluorescence spectroscopy, UV-Vis spectroscopy, FT-IR spectroscopy, nuclear magnetic resonance (NMR) and complex model analysis. The interaction between different MW DOM and NP was verified by the spectral characterization data. According to the characterization analysis, the main components of DOM in water samples were proteinoid (C1, C2, C4) with MW < 1 k Da, and their binding capacity (log Ka value) and binding site number (n) showed the maximum values (3.37, 3.24, 3.26; 0.81, 1.22, 0.52). For the humus like substance (C3) with larger molecular weight, the log Ka value and the number of binding points n increased with increasing molecular weight, and the maximum values were 3.13 and 0.31, respectively. It can be seen that low molecular weight proteins have strong binding ability and binding sites with NP, and high molecular weight humus also have strong binding ability. Overall, the interaction between DOM and NP has molecular weight dependence and heterogeneity. The purpose of this study is to deeply understand the interaction characteristics of different MW DOM with NP, and to provide theoretical support and reference for the study of the removal effects of NP pollutants.

Soybean Isoflavones Alleviate Osteoarthritis Through Modulation of the TSC1/mTORC1 Signaling Pathway to Reduce Intrachondral Angiogenesis.

BACKGROUND: The incidence of osteoarthritis (OA) is increasing, yet its pathogenesis remains largely unknown. Recent studies suggest that abnormal subchondral bone remodeling plays a crucial role in OA development, highlighting a gap in clinical treatments targeting this aspect. Soybean Isoflavone (SI) has shown potential in treating OA, although its mechanisms are not fully understood. METHODS: This research investigated the effects of SI on subchondral bone remodeling in an OA rat model, assessing joint damage, OARSI scores, and type H vessel formation (CD31hiEmcnhi expression). Additionally, the expression of ALP, OCN, BMP, and TSC1 was evaluated to determine involvement of the mTORC1 pathway. In vitro studies on IL-1ß-induced osteoblasts further examined the impact of SI on TSC1/mTORC1 signaling and related markers. RESULTS: SI treatment reduced joint damage and OARSI scores in the rat OA model, significantly decreasing CD31hiEmcnhi expression, indicating a reduction in type H vessel formation. SI also downregulated ALP, OCN, and BMP expression while upregulating TSC1, suggesting inhibition of the mTORC1 signaling pathway and VEGF release. In vitro, SI increased TSC1 expression and decreased mTORC1 signaling, VEGF, ALP, OCN, and BMP levels in IL-1ß-induced osteoblasts. CONCLUSION: SI targets the TSC1/mTORC1 signaling pathway to suppress osteoblast activation and VEGF release, inhibiting type H vessel formation and slowing abnormal subchondral bone remodeling. These findings provide a novel therapeutic approach for OA by focusing on subchondral bone remodeling mechanisms.

Recombinant filaggrin-2 improves skin barrier function and attenuates ultraviolet B (UVB) irradiation-induced epidermal barrier disruption.

The integrity of the skin barrier is essential for maintaining skin health, with the stratum corneum and filaggrin 2 (FLG-2) playing a key role. FLG-2 deficiency or mutation has been linked to diseases such as atopic dermatitis, while external stressors such as ultraviolet B (UVB) radiation further damage the epidermal barrier. This study investigated the effects of recombinant filaggrin (rFLG) on skin barrier function and UVB induced epidermal destruction. Cell experiments showed that 10 µg/mL of rFLG could increase the mobility of HaCaT cells from 20 % to 42 %, increase the epithelial resistance (TEER) value by about 2 times, and up-regulate the tight junction associated protein by about 2 times. In mouse models of UVB-induced epidermal barrier destruction, rFLG at concentrations of 0.5, 1, and 2 mg/mL showed effective cell uptake and skin penetration, alleviating erythema, and reducing skin thickness in mice by 1.5-3 times. Among them, 2 mg/mL of rFLG treatment restored the expression of tight junction proteins (LOR, ZO-1, and caspase-14), reduced collagen degradation, and reduced oxidative stress by normalizing serum hydroxyproline and superoxide dismutase levels. In addition, 2 mg/mL of rFLG inhibited UVB-induced upregulation of matrix metalloproteinases (MMP-3 and MMP-9) and reduced pro-inflammatory factors (IL-10, IL-1α, IL-6, and TNF-α) and apoptotic markers (P38, Bax, and Bcl-2) to normal levels. These findings suggested that rFLG effectively enhanced skin barrier integrity and mitigated UVB-induced epidermal barrier destruction, highlighting its potential as a therapeutic agent for diseases associated with skin barrier dysfunction.

Melatonin Attenuates Diabetic Retinopathy by Regulating EndMT of Retinal Vascular Endothelial Cells via Inhibiting the HDAC7/FOXO1/ZEB1 Axis.

Diabetic retinopathy (DR) is characterized as a microvascular disease. Nonproliferative diabetic retinopathy (NPDR) presents with alterations in retinal blood flow and vascular permeability, thickening of the basement membrane, loss of pericytes, and formation of acellular capillaries. Endothelial-mesenchymal transition (EndMT) of retinal microvessels may play a critical role in advancing NPDR. Melatonin, a hormone primarily secreted by the pineal gland, is a promising therapeutic for DR. This study explored the EndMT in retinal microvessels of NPDR and its related mechanisms. The effect of melatonin on the retina of diabetic rats was evaluated by electroretinogram (ERG) and histopathologic slide staining. Furthermore, the effect of melatonin on human retinal microvascular endothelial cells (HRMECs) was detected by EdU incorporation assay, scratch assay, transwell assay, and tube formation test. Techniques such as RNA-sequencing, overexpression or knockdown of target genes, extraction of cytoplasmic and nuclear protein, co-immunoprecipitation (co-IP), and multiplex immunofluorescence facilitated the exploration of the mechanisms involved. Our findings reveal, for the first time, that melatonin attenuates diabetic retinopathy by regulating EndMT of retinal vascular endothelial cells via inhibiting the HDAC7/FOXO1/ZEB1 axis. Collectively, these results suggest that melatonin holds potential as a therapeutic strategy to reduce retinal vascular damage and protect vision in NPDR.

Histone deacetylases: Regulation of vascular homeostasis via endothelial cells and vascular smooth muscle cells and the role in vascular pathogenesis.

Histone deacetylases (HDACs) are proteases that play a key role in chromosome structural modification and gene expression regulation, and the involvement of HDACs in cancer, the nervous system, and the metabolic and immune system has been well reviewed. Our understanding of the function of HDACs in the vascular system has recently progressed, and a significant variety of HDAC inhibitors have been shown to be effective in the treatment of vascular diseases. However, few reviews have focused on the role of HDACs in the vascular system. In this study, the role of HDACs in the regulation of the vascular system mainly involving endothelial cells and vascular smooth muscle cells was discussed based on recent updates, and the role of HDACs in different vascular pathogenesis was summarized as well. Furthermore, the therapeutic effects and prospects of HDAC inhibitors were also addressed in this review.

Lead-Free Cs2AgBiBr6/TiO2 S-Scheme Heterojunction for Efficient Photocatalytic Antibiotic Rifampicin Degradation.

Exploring efficient and stable halide perovskite-based photocatalysts is a great challenge due to the balance between the photocatalytic performance, toxicity, and intrinsic chemical instability of the materials. Here, the environmentally friendly lead-free perovskite Cs2AgBiBr6 confined in the mesoporous TiO2 crystal matrix has been designed to enhance the charge carrier extraction and utilization for efficient photocatalytic rifampicin degradation. The as-prepared Cs2AgBiBr6/TiO2 catalyst was stable in air for over 500 days. An S-scheme heterojunction was formed between the (004) plane of Cs2AgBiBr6 and the (101) plane of TiO2 through the Bi-O-Br bonds. The built-in electric field at the interface efficiently promoted the photoinduced charge separation and carrier extraction. The Cs2AgBiBr6/TiO2-200 showed a 92.83% degradation efficiency of rifampicin within 80 min under simulated sunlight illumination (AM 1.5G 100 mW cm-2). This work offers an effective way for the construction of halide perovskite-based photocatalysts with high photocatalytic performance, good stability, and low toxicity simultaneously.

Bubble-Guidance Breaking Gas Shield for Highly Efficient Overall Water Splitting.

Overall water splitting is a promising technology for sustainable hydrogen production, but the primary challenge is removing bubbles from the electrode surface quickly to increase hydrogen production. Inspired by the directional fluid transport properties of natural biological surfaces like Nepenthes peristome and Morpho butterfly's wings, here a strategy is demonstrated to achieve highly efficient overall water splitting by a bubble-guidance electrode, that is, an anisotropic groove-micro/nanostructured porous electrode (GMPE). Gradient groove micro/nanostructures on the GMPE serve as high-speed bubble transmission channels and exhibit superior bubble-guidance capabilities. The synergistic effect of the asymmetric Laplace pressure generated between microscale porous structure and groove patterns and the buoyancy along the groove patterns pushes the produced bubbles directionally to spread, transport, and detach from the electrode surface in time. Moreover, the low adhesive nanosheet arrays are beneficial to reduce bubble size and increase bubble release frequency, which cooperatively improve mass transfer with the microscale structure. Notably, GMPE outperforms planar-micro/nanostructured porous electrode (PMPE) in hydrogen/oxygen evolution reactions, with GMPE||GMPE showing better water splitting performance than commercially available RuO2||20 wt.% Pt/C. This work improves electrodes for better mass transfer and kinetics in electrochemical reactions at solid-liquid-gas interfaces, offering insight for designing and preparing gas-involved photoelectrochemical electrodes.

Impurity Level-Induced Broadband Photoelectric Response in Wide-Bandgap Semiconductor SrSnO3.

Broadband spectrum detectors exhibit great promise in fields such as multispectral imaging and optical communications. Despite significant progress, challenges like materials instability in such devices, complex manufacturing process, and high cost still hinder their further application. Here, we present a method that achieves broadband spectral detection by impurity-level in SrSnO3. We report over 500 mA/W photoresponsivity at 275 nm (ultraviolet C solar-bind) and 367 nm (ultraviolet A) and ∼60 mA/W photoresponsivity at 532 and 700 nm (visible) with a voltage bias of -5 V. Further transport and photoluminescence results reveal a new phase transition at 88 K, which would significantly affect the impurity level of the La-doped SrSnO3 film, indicating that the broadband response attributes to the impurity levels and mutual interactions. Additionally, the photodetector demonstrates excellent robustness and stability under repeated tests and prolonged exposure in air. These findings show the potential of SrSnO3 as a material for photodetectors and propose a method to achieve broadband spectrum detection, creating new possibility for the development of single-phase, low-cost, simple structure, and high-efficiency photodetectors.

C3-Alkylation of Imidazo[1,2-a]pyridines via Three-Component Aza-Friedel-Crafts Reaction Catalyzed by Y(OTf)3.

As an important class of nitrogen-containing fused heterocyclic compounds, imidazo[1,2-a]pyridines often exhibit significant biological activities, such as analgesic, anticancer, antiosteoporosis, anxiolytic, etc. Using Y(OTf)3 as a Lewis acid catalyst, a simple and efficient method has been developed for the synthesis of C3-alkylated imidazo[1,2-a]pyridines through the three-component aza-Friedel-Crafts reaction of imidazo[1,2-a]pyridines, aldehydes, and amines in the normal air atmosphere without the protection of inert gas and special requirements for anhydrous and anaerobic conditions. A series of imidazo[1,2-a]pyridine derivatives were obtained with moderate to good yields, and their structures were confirmed by 1H NMR, 13C NMR, and HRMS. Furthermore, this conversion has the advantages of simple operation, excellent functional group tolerance, high atomic economy, broad substrate scope, and can achieve gram-level reactions. Notably, this methodology may be conveniently applied to the further design and rapid synthesis of potential biologically active imidazo[1,2-a]pyridines with multifunctional groups.

Oxysulfonylation of Alkynes with Sodium Sulfinates to Access ß-Keto Sulfones Catalyzed by BF3·OEt2.

An efficient and operationally simple method for the synthesis of ß-keto sulfones through the BF3·OEt2-promoted reaction of alkynes and sodium sulfinates is developed. With its facile and selective access to the targets, it features good functional group compatibility, mild conditions, easily available starting materials, and good yields. Notably, the reaction does not require metal catalysts or chemical reagents with pungent odors.

Dermal Injection of Recombinant Filaggrin-2 Ameliorates UVB-Induced Epidermal Barrier Dysfunction and Photoaging.

The epidermal barrier is vital for protecting the skin from environmental stressors and ultraviolet (UV) radiation. Filaggrin-2 (FLG2), a critical protein in the stratum corneum, plays a significant role in maintaining skin barrier homeostasis. However, the precise role of FLG2 in mitigating the adverse effects of UV-induced barrier disruption and photoaging remains poorly understood. In this study, we revealed that UVB exposure resulted in a decreased expression of FLG2 in HaCaT keratinocytes, which correlated with a compromised barrier function. The administration of recombinant filaggrin-2 (rFLG2) enhanced keratinocyte differentiation, bolstered barrier integrity, and offered protection against apoptosis and oxidative stress induced by UVB irradiation. Furthermore, in a UV-induced photodamage murine model, the dermal injection of rFLG2 facilitated the enhanced restoration of the epidermal barrier, decreased oxidative stress and inflammation, and mitigated the collagen degradation that is typical of photoaging. Collectively, our findings suggested that targeting FLG2 could be a strategic approach to prevent and treat skin barrier dysfunction and combat the aging effects associated with photoaging. rFLG2 emerges as a potentially viable therapy for maintaining skin health and preventing skin aging processes amplified by photodamage.

Association of periodontitis with cardiovascular and all-cause mortality in hypertensive individuals: insights from a NHANES cohort study.

BACKGROUND: The objective of this research is to clarify the impact of periodontitis on overall and cardiovascular-related death rates among hypertensive individuals. METHOD: A total of 5665 individuals with hypertension were included from the National Health and Nutrition Examination Survey (NHANES) data spanning 2001-2004 and 2009-2014. These individuals were divided into two groups based on the presence or absence of periodontitis and further stratified by the severity of periodontitis. We employed weighted multivariate Cox proportional hazards regression and Kaplan-Meier curves (log-rank test) to evaluate the impact of periodontitis on all-cause and cardiovascular mortality. Additional analyses, including adjustments for various covariates, subgroups, and sensitivity analyses, were conducted to ensure the robustness and reliability of our results. RESULT: Over an average follow-up duration of 10.22 years, there were 1,122 all-cause and 297 cardiovascular deaths. Individuals with periodontitis exhibited an elevated risk of all-cause mortality (HR = 1.33, 95% CI 1.18-1.51; p < 0.0001) and cardiovascular mortality (HR = 1.48, 95% CI 1.15-1.89; p = 0.002). Moreover, we observed a progressive increase in both all-cause mortality and cardiovascular mortality (p for trend are both lower than 0.001) and correlating with the severity of periodontitis. These associations remained consistent across various subgroup and sensitivity analyses. CONCLUSION: Our findings suggest a significant association between periodontitis and increased risks of all-cause and cardiovascular mortality among hypertensive individuals. Notably, the severity of periodontitis appears to be a critical factor, with moderate to severe cases exerting a more pronounced impact on all-cause mortality. Additionally, cardiovascular disease mortality significantlly increases in individuals with varying degrees of periodontitis.

Macrophage ILF3 promotes abdominal aortic aneurysm by inducing inflammatory imbalance in male mice.

Imbalance of proinflammatory and anti-inflammatory responses plays a crucial role in the progression of abdominal aortic aneurysms. ILF3, a known modulator of the innate immune response, is involved in cardiovascular diseases. This study aims to investigate the role of ILF3 in abdominal aortic aneurysm formation. Here, we use multi-omics analyzes, transgenic male mice, and multiplex immunohistochemistry to unravel the underlying involvement of ILF3 in abdominal aortic aneurysms. The results show that macrophage ILF3 deficiency attenuates abdominal aortic aneurysm progression, while elevated macrophage ILF3 exacerbates abdominal aortic aneurysm lesions. Mechanistically, we reveal that macrophagic ILF3 increases NF-κB activity by hastening the decay of p105 mRNA, leading to amplified inflammation in macrophages. Meanwhile, ILF3 represses the anti-inflammatory action by inhibiting the Keap1-Nrf2 signaling pathway through facilitating the ILF3/eIF4A1 complex-mediated enhancement of Keap1 translational efficiency. Moreover, Bardoxolone Methyl treatment alleviates the severity of abdominal aortic aneurysm lesions in the context of elevated ILF3 expression. Together, our findings underscore the significance of macrophage ILF3 in abdominal aortic aneurysm development and suggest its potential as a promising therapeutic target for abdominal aortic aneurysms.

STAC3 as a poor prognostic biomarker in renal clear cell carcinoma: relationship with immune infiltration.

Calcium ions (Ca2+) are crucial in tumorigenesis and progression, with their elevated levels indicating a negative prognosis in Kidney Renal Clear Cell Carcinoma (KIRC). The influence of genes regulating calcium ions on the survival outcomes of KIRC patients and their interaction with the tumor's immune microenvironment is yet to be fully understood. This study analyzed gene expression data from KIRC tumor and adjacent non-tumor tissues using the TCGA-KIRC dataset to pinpoint genes that are differentially expressed in KIRC. Intersection of these genes with those regulating calcium ions highlighted specific calcium ion-regulating genes that exhibit differential expression in KIRC. Subsequently, prognostic risk models were developed using univariate Cox and LASSO-Cox regression analyses to verify their diagnostic precision. Additionally, the study investigated the correlation between tumor immunity and KIRC patient outcomes, assessing the contribution of STAC3 genes to tumor immunity. Further exploration entailed SSGASE, single-cell analysis, pseudotime analysis and both in vivo and in vitro experiments to evaluate STAC3's role in tumor immunity and progression. Notably, STAC3 was significantly overexpressed in tumor specimens and positively correlated with the degree of malignancy of KIRC, affecting patients' prognosis. Elevated STAC3 expression correlated with enhanced immune infiltration in KIRC tumors. Furthermore, silencing STAC3 curtailed KIRC cell proliferation, migration, invasion, and stemness properties. Experimental models in mice confirmed that STAC3 knockdown led to a reduction in tumor growth. Elevated STAC3 expression is intricately linked with immune infiltration in KIRC tumors, as well as with the aggressive biological behaviors of tumor cells, including their proliferation, migration, and invasion. Targeting STAC3 presents a promising strategy to augment the efficacy of current therapeutic approaches and to better the survival outcomes of patients with KIRC.

Panthenol Additives with Multiple Coordination Sites Induce Uniform Zinc Deposition and Inhibited Side Reactions for High Performance Aqueous Zinc Metal Battery.

Application of aqueous zinc metal batteries (AZMBs) in large-scale new energy systems (NESs) is challenging owing to the growth of dendrites and frequent side reactions. Here, this study proposes the use of Panthenol (PB) as an electrolyte additive in AZMBs to achieve highly reversible zinc plating/stripping processes and suppressed side reactions. The PB structure is rich in polar groups, which led to the formation of a strong hydrogen bonding network of PB-H2O, while the PB molecule also builds a multi-coordination solvated structure, which inhibits water activity and reduces side reactions. Simultaneously, PB and OTF- decomposition, in situ formation of SEI layer with stable organic-inorganic hybrid ZnF2-ZnS interphase on Zn anode electrode, can inhibit water penetration into Zn and homogenize the Zn2+ plating. The effect of the thickness of the SEI layer on the deposition of Zn ions in the battery is also investigated. Hence, this comprehensive regulation strategy contributes to a long cycle life of 2300 h for Zn//Zn cells assembled with electrolytes containing PB additives. And the assembled Zn//NH4V4O10 pouch cells with homemade modules exhibit stable cycling performance and high capacity retention. Therefore, the proposed electrolyte modification strategy provides new ideas for AZMBs and other metal batteries.

A gain-of-function variant in SREBF1 causes generalized skin hyperpigmentation with congenital cataracts.

BACKGROUND: Lipid metabolism has essential roles in skin barrier formation and the regulation of skin inflammation. Lipid homeostasis regulates skin melanogenesis, although the underlying mechanism remains largely unknown. Sterol regulatory element binding protein 1 (SREBP-1) is a key transcription factor essential for cellular lipid metabolism. Loss-of-function variants in SREBF1 are responsible for autosomal-dominant ichthyosis follicularis, alopecia and photophobia syndrome, emphasizing the significance of lipid homeostasis in skin keratinization. OBJECTIVES: To identify the genetic basis of a new entity featuring diffuse skin hyperpigmentation with congenital cataracts, and to unravel the underlying mechanism for the pathogenesis of the SREBF1 variant. METHODS: Whole-exome sequencing was performed to identify underlying genetic variants. Quantitative polymerase chain reaction, Western blot and immunofluorescence staining were used to assess the expression and the subcellular localization of the SREBF1 variant. The transcriptional activity of mutant SREBP-1 was determined by a luciferase reporter assay. A transgenic zebrafish model was constructed. RESULTS: Two unrelated patients presented with generalized skin hyperpigmentation with skin xerosis, congenital cataracts and extracutaneous symptoms. We identified a de novo nonsense variant c.1289C>A (p.Ser430*) in SREBF1 in both patients. The variant encoded a truncated protein that showed preferential nucleus localization, in contrast to wild-type SREBP-1 which - in sterol-sufficient conditions - is mainly localized in the cytoplasm. The luciferase reporter assay revealed that the p.Ser430* mutant exhibited enhanced transcriptional activity. Cultured patient primary melanocytes showed increased melanin synthesis vs. those from healthy controls. At 35 days postfertilization, the p.Ser430* transgenic zebrafish model exhibited more black spots, along with upregulated expression of melanogenic genes. CONCLUSIONS: We demonstrated that a gain-of-function variant of SREBF1 causes a previously undescribed disorder characterized by generalized skin hyperpigmentation and congenital cataracts. Our study reveals the involvement of SREBP-1 in melanogenesis and lens development, and paves the way for the development of novel therapeutic targets for skin dyspigmentation or cataracts.

The genetic basis of many diseases that cause skin hyperpigmentation are not fully understood. Hyperpigmentation means that some patches of skin are darker than others. This is caused by the overproduction of a pigment called melanin. We report on two patients who were born with skin hyperpigmentation and cataracts. The cause of the patients' disease was unknown, so we carried out genetic testing in the patients. The tests showed that both patients had a change ('mutation') in a gene called 'SREBF1'. This gene encodes for a protein called SREBF-1. Other mutations in this protein are involved in other skin diseases. A different test showed that the mutated SREBF1 gene was activated more often than normal. Skin cells taken from both patients also produced more pigment than cells taken from people without hyperpigmentation. To confirm this gene mutation causes more skin pigmentation, we did an experiment with zebrafish with the same mutation. At 35 days after fertilization, the zebrafish showed more black spots on their skin. Our study reveals the involvement of SREBP-1 in the production of melanin and lens development in the eye. The findings may offer a new approach to treating hyperpigmentation in skin diseases.